Pregnane and allopregnane-11alpha, 21-diol-3, 20-diones and process



Unite PREGNANE AND ALLQPREGNAWE-llaJl-DKOL- 3,20-D10NES AND PRGCESS NoDrawing. Application February 6, 1953 Serial No. 335,585

Claims priority, application Mexico February 13, 1952 11 (Iiaims. (Ci.260397.45)

The present invention relates to novel cyclopentanophenanthrenecompounds and to a novel process for the production thereof.

More particularly the present invention relates to novel compounds ofthe allopregnane series having hydroxy groups in the 110: and 21positions, a keto group in the 3- position and esters of these compoundsas well as a novel method for the production of these aforementionedcompounds. The present invention also relates to certain novelintermediates for the production of the compounds just referred to suchas allopregnene compounds provided with a 20 acetoxy group and a 20-21double bond or a 21 bromo substituent. The novel compounds of thepresent invention are valuable intermediates for the production of 11oxygenated cortical hormones as will be hereinafter set forth.

In our United States patent application Serial Number 307,722, filedSeptember 3, 1952, there has been described a method for the preparationof 20-enol acetates of allopregnan-3fi,l1a-dio1-20-one compounds havinga double bond between carbon atoms -17 and C-20 by treating thecorresponding allopregnan-3B, llu-diol-20- one with acetic anhydride inthe presence of a strong acid such as p-toluene sulfonic acid.

In accordance with the present invention the surprising discovery hasbeen made that when the same compounds i. e. allopregnane-3B,l1a-20-oneand/or esters thereof are treated with isopropenyl acetate in thepresence of a strong acid as a catalyst different novel enol acetateshaving a double bond between carbon atoms (3-20 and C-21 are formed. Ithas further been discovered that this novel enol acetate may betransformed into States Patent the isomer described in theaforementioned application a by refluxing the same with acetic anhydrideand p-toluenesulfonic acid. Further, the new enol acetate of the presentapplication may be easily brominated to produce the corresponding21-bromo compounds which on treatment for a short period with sodiumiodide in a lower ketone, such as acetone solution, followed bytreatment with potassium acetate yields the corresponding ZI-acetate, asfor example, the triacetate of allopregnan-Bfl,11a,21- triol-20-one.

The novel 2l-acetate just referred to may be saponitied in accordancewith the present invention and the saponification may be followed by amild acetylation to form the 2l-monoacetate ofallopregnan-3B,l1a,2l-triol- ZO-one. In the alternative hydrolysis inacid medium produces the ll-mono-acetate of allopregnan-BBJh-diol-20-one brominated in the 21 position which on treatment with sodiumiodide in a lower ketone such as acetone followed by treatment withpotassium acetate gave the corresponding 11a,2l-diacetate ofallopregnan-3B,1lu,21- triol-ZO-one or the equivalent lla-acylate wherethe 11mhydroxy group has been acylated with another acid residue.

Still another method has been provided in accordance with the presentinvention for the transformation of csconverted in accordance with thepresent invention into allopregnan-l1a,2l-diol-3,20-dione and/or itsesters.

The following equation serves to illustrate in part the process of thepresent invention:

RQ- v l l Isopropenyl I acetate (1 Strong aci R 0 catalyst; R0 iBromination (I /H3 v =0 (|JHgBl' G=O H 0- m l H OQi Acid hydrolysis$Hg-O R (3112-131- C=O 0 0.

O= HO 4 Strong saponification Sodium iodide followed by mild potassiumacylation acetate C|H -OA0 CHz-OAG (7:0 =0 IQ lfi Oxidation In the aboveequation, R is an acyl group, preferably the residue of a lower fattyacid such as acetic acid or propionic acid or an aromatic acid,preferably benzoic acid. Ac in the above equation represents the acetylradical.

In practicing the process above outlined, a diester ofa1lopregnan-3B,llwdiol-20-one such as the diacetate or the dibenzoatethereof, or the free dial is refluxed with a small amount of isopropenylacetate for a short period of time, as for example three and one-halfhours, in the presence of a catalytic amount of a strong acid such asconcentrated sulfuric acid or p-toluenesulfonic acid. At the end of thistime, a further quantity of isopropenyl acetate and a limited amount ofstrong acid is added and ,ing equation:

the s'olutionisfioiitriititd to one-third of its original volume. "Theconcentrated reaction solution 'is then poured into ice and theprecipitate formed extracted with a suitable solvent suchas ether,purified-dried and "evaporated under a vacuum until all ft'racesjerthe-iso- "proper'iyl acetate'ivre eliminated. Upon" purification, "ashereinafter set for'thjn'the specificexamples, "theciyStaI .linejp"3'B,Ileig2fi triol trictater i V V V t The A -allopregnene -'3,8,11a,20triol-trica'tate' could be converted into thecorrespondingA-allopregnene- 3fi,1la-,20-triol triacetate described in the previouslymentioned patent application by adding thereto p-toluenesulfonic acid-inacetic anhydride and slowly concentrating the reaction solution for aperiod of four hours f 'to a small volume, as hereinafter described indetail.

7 The A -enOI acetate formed infiaccordance with the first referredtostep' could be -readily brominated by treating a solution of theenoljacetat'e ina suitable-solvent such as carbontetrachloride with amol'equivalent of bromine in carbon tetrachloride; As soon as thereactiomsolution decolorized, it Was immediately evaporated underreduced pressure and the residue was then dissolved in methanol and asmall amount of concentrated hydrochloric acid added thereto. Afterstanding at room temperature for approximately one day'the mixture wasthenpouredinto dilute sodium bicarbonate solution, the precipitateextracted with ether, purified and evaporated to dryness. The residue,upon crystallization from methanol 'gave'the 21-bromo-1l-monoacetate, asfor example, 21-bromo-allopregnan-3,8,llot-diol 20 one --1 1-monoacetate. Theatment of the monoacet'ate with sodium iodide inthepresence of a lower alkyl ketone; such as acetone, followed byfiltration of the sodium bromide formed, and refluxing for approximatelyone day with potassiumbicarbonate and acetic acid, produced thecorresponding 11,21 diacetate, as for example, allopregnan-3B,1-1u,21-triol-20-one-11,21 diacetate.

The allopregnan-3fi,11a,21-triol- 2O one 11,21-diacetate as wellvasother diesters of the same compound such as, for example; thedibenzoate, may also be prepared by an alterantive method to behereinafter described in detail. In any event, these diesters may betransformed into the corresponding 3-keto compounds, by oxidizing thesame with an oxidizing agent'such as chromic acid in acetic acid.Thisoxidation produced, forexamplefallopregnan-1la,2l-diol-3,20 dionediacetate. In place of chromic acid, other oxidizing agents such asN-bromoacetamidefor aluminum t-butylate orisopropylate in the presenceof a hydrogen acceptor, could be utilized. 2 Finally, the diacylate ofallopre'g'nan-l 1u,21-diol-3,20- dione could be saponified as forexample with methanolic potassium hydroxide to form the correspondingallopregnan-l1a,21 diol 3,20 dione. 'A mild acetylation of this freecompound or other acylation with slightly over l -mol equivalent of asuitableanhydride such as acetic anhydride in pyridine would thenproduce the 21- monoacylate of allopregnan-1-1-u,21-diol-3,20-dione.

The present invention also contemplates thelproduetion of certain noveltriesters as well as 21-monoesters'of allo- -pregnan-3fi,11c,21-triol 20one, as for example the tri- Iacet'a'teithereof. This reaction isillustrated by thefollow- Sodium iodide Potassium acetate no nodductiisj formedfas forexampie x -"auopre nenesaponification followed bymild acylatlon l Alkaline ,In the above, equation R represents the sameacyl groupsas previously'set forth. Ac-represents acetate.

, In practicing the process just above outlined, the 21-bromo-allopregnan-3fl,lla-diol-ZO-one 'diacylate, such as the diacetate.prepared aspreviously set forth is dissolved hydroxide produced thecorresponding free compound allopregnan iap,llaJI-triOI-ZO one and thiscompound could; be conventionally acylated 'with a 'suitableacid.anhydride in the presence of pyridine to= give'the 'corresponding;ZI-monoacylate such as the 21-monoacetate.

Another process for therproduction of -1l,21-diester.;of allopregnane-35,1 10:; Qhtriol-ZO-one-from a corresponding rdiester of allopregnane-iiil1adiol-20-one, such as the ,diacetate-or the dibenzoate, isillustrated in the-following equation: t 7

GHi-OAc Y Oxidation ead tetraeetate i lPartial' 59 v .1 a f; ,j'Sap0nification.

: g V v. V v ,CH OH a V J1VCV=O no 5:; V Mile 7 t t Eaeylation B01 l no6G H In 'th ei above {equation R "represents thc' s anie '"acyl'g'roupsiasherinbefore stated. Ac 'represents"acetat e. Vlnpr'acticingthe process as above outlined, a suitable g'diesterof'allopregnane/illei-diol-ZO one, such' as the diacetate or thedibriz'oate isdissolved'in glacial acetic; acid,

a and heated to ithe boiling point, thereafter lead tetr'acetate 'inacetic'acidis added slowly to the'boiling solution. "As'soonastlieadditioniscomplete, as for example about o'nej'and nehalf hours, the solutionisimmediately cooled 'and diluted'withw'ater. Extraction of the productwith a a suitable s'olventsfuchas' ether, purification ofthe solution,diying'thereofandevaporation toldryriessfollowed Eyre,crystallization'from a suitable solvent such as hexane ace: flf'to'ne,jprodiiced allopre'gnan 3,8,l'la-2l triol-20 orie triin: a 'su'itable,lower ketone solvent such as acetone and a acetate in the case of thediacetate starting material and the corresponding 3,11-dibenzonateZl-acetate of allopregname-3,8,1la,21-triol-2G-one in the case of thedibenzoate starting material. A further portion of the product wasobtained by refluxing the mother liquor with alcohol, semicarbazidehydrochloride and sodium acetate to form the semicarbazone of thestarting material which was filtered from the solution. The solution wasthen evaporated to dryness and the product recrystallized from acetonehexane to give an additional amount of the triester.

The triester thus produced could be partially saponified by refluxing analcoholic solution thereof for a short time with an alkali metalcarbonate, such as sodium or potassium bicarbonate. Concentration of thereaction solution under vacuum, purification and recrystallizationproduced the ll-monoester of allopregnan-Zlfld1a,21-triol-20-one, suchas the ll-monoacetate or the ll-monobenzoate.

The monoester prepared in accordance with the preceding step could beconverted to the corresponding 11,21- diester by a mild acylation with asuitable acid anhydride such as a lower fatty acid anhydride or benzoicacid anhydride in the presence of pyridine. For this purpose, themonoester is dissolved in the pyridine and treated with slightly morethan a molar equivalent of a suitable anhydride, such as aceticanhydride, at a low temperature for approximately 24 hours. Purificationof the product produced allopregnan-3 18,1 1a.,21-tIiOl-20-Ol1E-11,2l-diacetate.

As will be apparent from the foregoing description, there is prepared inaccordance with the above process the novel and valuable final products,namely the 21-monoesters of allopregnan-l1a,21-diol-3,20-dione, such asthe ill-acetate. These are novel and valuable intermediates for theproduction of the corresponding novel Ila-isomer of the cortical hormonecorticosterone since it difiers from this llu-isorner only in its ring Asaturated structure. This structure may be readily provided bydibromination at positions C-2 and C-4 of ring A, followed by treatmentwith sodium iodide to form the 2-iodo-3-keto-A structure in ring A andfinally by removal of the iodine by a dehalogenating agent such as zincdust in acetic acid as described in greater detail in our United Statesapplication Serial No. 218,095, filed March 28, 1951. Further, the 21ester of the lla-isomer of corticosterone may be readily oxidized by amild oxidizing agent such as chromic anhydride under mild conditions tothe known adrenal cortical hormone compound ll-dehydrocorticosterone(Fieser & Fieser, Natural Products Related to Phenanthrene, thirdedition, pages 444 and 445).

There is also described as a final product and valuable intermediatesthe 2l-monoesters of allopregnan-3fi,l la,2ltriol-ZO-one. This compoundmay also be readily oxidized to a 2l-mono ester ofallopregnan-2l-ol-3,l1,20- trione by using chromic anhydride. This lastcompound may be selectively reduced at the 3 position with sodiumborohydride to give the 21 mono ester of the known compound Reichsteinscompound N, which may be conventionally saponified to compound N. trionemay be also converted to 11 dehydrocorticosterone by providing thecompound With the 3-keto-A ring A structure by the previously outlinedmethod.

The following specific examples serve to illustrate but are not intendedto limit the present invention:

Example I A solution of 1 g. of allopregnan-3;3,1la-diol-ZO-onediacetate, or an equivalent amount of the free diol in 7 cc. ofisopropenyl acetate was refluxed during 3.5 hours in the presence of onedrop of concentrated sulphuric acid. After this time 3 cc. more ofisopropenyl acetate and one drop of sulphuric acid were added. Thesolution was concentrated to one third of its original volume, poured inice, and the precipitate was extracted with ether, washed with sodiumbicarbonate and water, dried over sodium sulphate and evaporated undervacuum until all traces of isopropenyl acetate were eliminated.- Thelight brown oil In the alternative the I which remained as a residue wasdissolved in hexane and the solution was passed through a column of 30g. of alumina previously washed with ethyl acetate. The column was thenwashed with an additional amount of hexane and the eluted solution wasconcentrated to give colorless crystals of the A-allopregnen-3fl,11a,20-triol triacetate.

Example II A solution of 1 g. of allopregnan-3fl,1la-diol-ZO-onediacetate was treated in exactly the same way as described in Example 1except that 400 mg. of p-toluenesulphonic acid were used instead of thedrop of sulphuric acid. The same compound was obtained as in theprevious example.

Example 111 A solution or" 500 mg. of A -allopregnen-3B,lla,20- trioltriacetate and 500 mg. of p-toluenesulphonic acid in 50 cc. of aceticanhydride was slowly concentrated in the course of 4 hours to a volumeof 15 cc. The mixture was poured in ice water and then treated in thesame way as described in Example I yielding the enol acetate with thedouble bond at 17 (A -allopregnen-3B,l1a,20- triol triacetate, describedin our previously mentioned patent application) the structure of whichwas proved by conversion into allopregnan-Bfidla,l7a-triol-20-one bytreatment with perbenzoic acid and alkali according to the descriptiongiven in the above-mentioned patent application.

Example IV A solution of bromine (the equivalent of 1 mol) in carbontetrachloride was added dropwise to a solution of 2.5 g. of the enolacetate of Example I in cc. of carbon tetrachloride. The solutiondecolorized rapidly and it was immediately evaporated under reducedpressure. The residue was dissolved in 80 cc. of acetone and refluxedfor 15 minutes with 1.5 g. of sodium iodide. The sodium bromide formedwas filtered and the solution was refluxed during 6-12 hours with 12.5g. of potassium bicarbonate and 7.5 cc. of acetic acid. Water was addedand the product was extracted with ether, washed with sodium bicarbonateand water, dried over sodium sulphate and evaporated to dryness.Crystallization from hexane-acetone yielded allopregnan-iiphllu,2l-triol-20-one triacetate.

Example V A solution of 1.4 g. of 2l-bromo-allopregnan-3B,lladiol-ZO-onediacetate (such as obtained upon evaporation of the carbon tetrachloridesolution, according to Example 1V) in cc. of methanol and 1.4 cc. ofconcentrated hydrochloric acid was left standing at room temperatureduring 20 hours. The mixture was poured into dilute sodium bicarbonatesolution and the precipitate was extracted with ether, washed, dried andevaporated to dryness. The residue crystallized from methanol to give 21bromo-allopregnan 3 3,110: diol-20-one 11- monoacetate.

Example VI 1 g. of 2l-bromo-allopregnan-3,B,llwdiol-20-one llmonoacetatein 60 cc. of acetone was treated with 0.6 g. of sodium iodide and thenwith 4 g. of potassium bicarbonate and 2.4 cc. of acetic acid, followingthe method described in Example IV. In this manner allopregnan-3fl,lla,2l-triol-20-one 11,21-diacetate was obtained.

Example VII Ssponification of allopregnan 3fi,1la,21 triol-20-onetriacetate with methanolic potassium hydroxide under an atmosphere ornitrogen at room temperature during 24 hours, followed by precipitationwith water yielded allopregnan-3p,l1e,2l-triol-20-one which wasextracted with chloroform and crystallized in the usual way. Thiscompound was acetylated with 1.2 mols of acetic anhydride and pyridine,keeping the solution overnight at 7 a temperature between and C., togive the .ZI-monoacetate of allopregnan-3B,11a,21-triol-20-one.

ExdmpleVIII -A solution of l g. of lead tetracetate in cc. of aceticacid was added dropwise in'the. course of 90 minutes to a boilingsolution ofjl g. of allopregnan-3/3,l1 z-diol-20- one diacetate in cc.of glacial acetic acid. After the addition. was complete, the solutionwas immediately cooled and diluted with water. The product was extractedwith ether, washed'with sodium carbonate and water dried over sodiumsulphate and evaporated to dryness; Crystallization from hexane-acetoneafforded some allopregnau-3fi,1 lo:,2 l triol-Z0-one triacetate. Themother liquors were refluxed during 45 minutes with cc. of alcohol, 0.11g. of semicarbazide hydrochloride and 0.15 g. of sodium acetate. Thesolution was cooled and'theprecipitateof the semicarbazone of thestarting material was filtered. The solution was evaporated to drynessand recrystallized from acetone-hexane to give an-additional amount ofallopregnan-3{3,lic,2l-triol-20-- one triacetate.

The same reaction utilizing as the starting material the dibenzoateinstead of the diacetate of allopregnan- 313,1,l0t-dlOl-20-OI16, gavethe 3,1l-dibenzoate ZI-acetate of allopregnaue-35Jla,2l-triol-20-onehaving a melting point of 206-208 C.; [11],; +44 (chloroform).

Example IX An alcoholic solution of allopregnan-Iifidla,2l-triol- ZQ-onetriacetate was refluxed during 30 minutes with 2.3 molar equivalents ofsodium or potassium bicarbonate. The solution was concentrated undervacuum, poured into water and extracted with chloroform. The chloroformextract was washed, dried over sodium sulphate and evaporated todryness. Recrystallization from etherhexane yieldedallopregnan-StLlla,2l-triol20-one llrnonoacetate having a melting'pointof 230-236 (3.; [di +27".

' Example X The monoacetate obtained according to Example IX wasdissolved in pyridine and treated with 1.3 molar equivalents of aceticanhydride during 24 hours at a temperature between 0 and 5 C. Themixture was poured into water and left standing until the hydrolysis ofthe excess acetic anhydride was complete. The product was extracted withether, washed with sodium carbonate and water, dried over sodiumsulphate and evaporated to dryness. The residue was crystallized frommethanol to yield allopregnan-Lil1u,2l-triol-20 one ll,2l-diacetate.

Example XI aIlop'reg'nau-l 10:,21-(ll0l-3,20-dl011 diacetate.

Example XII 1.25 g. of allopregnan-3,8,lle,2l-triol-20-oneil,2i-diacetate wasdissolved in a mixture of 150 cc. of anhydroustoluene and 15 cc. of cyclohexanone and cc. of the solvent weredistilled in order to remove traces of moisture. A solution of 1.5 g. ofaluminum isopropylate in cc. of anhydrous toluene was added to theboiling solution in the course of 45 minutes. A slow distillation wasmaintained during all this time. The mixture was cooled and afteradding. 15 cc. of a concentrated solution of sodium potassium tartrate,it was subjected to steam distillation until removal of all the volatilecomponents. The residue wasextracted withether, washed; with water,

- which comprises treating dried over sodiumxsulplgate and evaporated toRecrystallization from ethyl acetate afiorded allopregnan llm,2 1-diol-3,20-dione diacetate, identical to the one obtained according toExample-IV.

Example XIII The diacetate-of allopregnan-l1m,21-diol-3,20-dione was VAcetylation with 1.2 molar equivalents of acetic anhydride in pyridinesolution during 24 hoursjat a temperature of 5 -l0 (3., followed by thetreatment described in Example ill yielded the 2l-monoacetate ofallopregnam 1l,21-diol-3,20-dione. r I t e 7 Although thepresent-process and the productsresule ing therefrom have beenillustrated by members of the allopregnane series, as well ascompoundshaving the 33- hydroxy configuration, thesesame methods areapplicable to compounds of the C-5 normal series, as well as compoundsprovided with a 3a-hydroxy group.

We claim: 7 p 1. A process for the production of 21-mono esters selectedfrom the class consisting of lower fatty acid esters and benzoic acidesters of a pregnan-llull-di ol- 3,2G-dione compound which comprisestreating an ;,21- diester selected from the class consisting of lowerfatty acid estersandbenzoiczacid esters ofa pregnan-3,11u,21-triol-ZO-one compound with an oxidizing'agent to form the corresponding-3-keto compound, treating the .3-keto compound with a saponifying agentto form the corre spending pregnan-llot,2l-diol-3,20-dione compound -andtreating said last mentioned'cornpound with approximately 1 mol of anacylating agent lower fatty acid anhydrides and benzoic acid anhydrideto selectively form the aforementioned 21-mono ester.

2. The process of claim 1 wherein the pounds are allopregnane'compounds.3. A method for the production of a diester selected from the classconsisting of lower fatty acid esters and benzoic acid esters of apregnane-lla,21-diol-3,20@di0nc, a corresponding 1l,21-die ster ofpregnan-3,1la,2l-triol-20-one with an oxidizing agent.

4; A method for the preparation of ll,21-diesters selected from theclass consisting of lower fatty acidesters and benzoic acid esters ofallopregnan-l1a,2l-diol 3,20- dione which comprises treating thecorresponding .1 1,21- diesters of alloprcgnan-3B,l1a,21-triol-20-onewith an oxidizing agent.

5. The method of claim 4 wherein is chromic acid.

6. The method of claim 4 is N-bromoacetamide.

pregnane comthe oxidizing agent wherein the oxidizing agent 7. Themethod of claim 4 wherein the oxidizing agent I is selected from theclass consisting of aluminum t-butylate and aluminum isopropylate in thepresence of ahydroge'n acceptor. 7

8. A new compound selected from the class consisting of apregnanla,2l-diol-3,20-dione, lower fatty acid and benzoic acid diestersthereof and lower fatty acid and benzoic acid 21-mono esters thereof.

9. A new compound consisting of allopregnan-lla,2ldiol -3,20-dionediacetate.

10. A new compound consisting of allopregnan-llm,2ldiol-3,20-dione.

11. A new compound consisting of allopregnan-l-la,2ldiol-3,2 0-dione21-monoacetate.

References Cited in the file of this patent FOREIGN PATENTS

1. A PROCESS FOR THE PRODUCTION OF 21-MONO ESTERS SELECTED FROM THECLASS CONSISTING OF LOWER FATTY ACID ESTERS AND BENZOIC ACID ESTERS OF APREGNAN-11A,21-DIOL3,20-DIONE COMPOUND WHICH COMPRISES TREATING AN11A,21DIESTER SELECTED FROM THE CLASS CONSISTING OF LOWER FATTY ACIDESTERS AND BENZOIC ACID ESTERS OF A PREGNAN-3,11A,21TRIOL-20-ONECOMPOUND WITH AN OXIDIZING AGENT TO FORM THE CORRESPONDING 3-KETOCOMPOUND, TREATING THE 3-KETO COMPOUND WITH A SAPONIFYING AGENT TO FORMTHE CORRESPONDING PREGNAN-11A,21-DIOL-3,20-DIONE COMPOUND AND TREATINGSAID LAST MENTIONED COMPOUND WITH APPROXIMATELY 1 MOL OF AN ACYLATINGAGENT LOWER FATTY ACID ANHYDRIDES AND BENZOIC ACID ANHYDRIDE TOSELECTIVELY FORM THE AFOREMENTIONED 21-MONO ESTER.